This invention relates to the generation of ultra-small liquid droplets. Droplets having volumes ranging in the tens of femtoliters are characterized here as ultra-small.
The ongoing advances in medicine and biotechnology are providing many effective and promising systemic therapies that call for the delivery of biological and chemical substances (such as peptides, proteins, and small molecules) to a patient""s bloodstream. There are various problems associated with getting certain substances to the bloodstream by conventional delivery means, such as transdermal and oral. For instance, oral delivery of therapeutic proteins does not work because the proteins are digested before they have an opportunity to reach the bloodstream. Thus, for this and other reasons, it is best to deliver such substances to the bloodstream by as direct a route as possible.
An aerosol is a gaseous suspension of very fine solid or liquid particles. Aerosols are presently used for delivering certain drugs to a patient""s lungs. Delivery of drugs or other therapeutic substances to a patient""s lungs is sometimes referred to as pulmonary delivery.
The innermost tissue of the lung is known as the alveolar epithelium, which comprises hundreds of millions of tiny air sacs, called alveoli, that are surrounded by a large network of blood capillaries. The alveoli enable rapid absorption of fluids from the alveoli to the bloodstream. Most effective pulmonary delivery is accomplished when the substance is delivered to the alveoli. The delivery process requires the generation of very small particles or droplets that can be entrained in a gas as an aerosol and inhaled by the patient into the alveoli for transfer to the bloodstream.
The lung""s alveoli can readily absorb liquid drops having diameters equal to or less than about 4 xcexcm, which represents a volume of about 33 femtoliters. A femtoliter is one quadrillionth (10xe2x88x9215) of a liter. Larger drops tend to contact the lung walls before reaching the alveoli and are less likely to permeate the wall to the bloodstream because the airway to the alveoli is lined with a thick, ciliated mucus-covered cell layer.
A popular pulmonary delivery mechanism is known as a metered dose inhaler (MDI). These are widely used for the delivery of asthma medication. While an MDI delivery system may be effective for medications designed to medicate the lung tissue, they are not optimal for delivery of substances to the alveoli (hence, to the bloodstream). In this regard, an MDI typically combines the drug with a propellant in a pressurized container. Actuation of the device releases metered doses of the aerosol, but the droplet size distribution is large, and the vapor pressure of the propellant varies with temperature and number of uses. Thus, the behavior of the material in the air stream and the extent to which droplets reach the alveoli becomes somewhat unpredictable.
In view of the foregoing, it can be appreciated that there is a need for a droplet generator that can reliably produce ultra-small-volume droplets with a generally uniform size distribution for entrainment in aerosols.
There exists the potential for generating very small droplets using a drop generator that is adapted from the kind employed in ink-jet printing. The type of ink-jet printing of interest here (often called thermal ink-jet printing) conducts ink into tiny chambers. Each chamber includes a heat transducer such as, for example, a thin-film resistor, to create a vapor bubble that ejects a droplet of ink through an orifice that overlies the chamber. The chambers and orifices are incorporated into a printhead device that is connected with a supply of ink and with a controller for timing the droplet ejection to reproduce images on media.
Current ink-jet designs provide drop generators that produce droplet volumes as small as about 4 picoliters, which is equivalent to 4,000 femtoliters. In order to produce droplets in the range of tens of femtoliters that, for example, can be entrained in an aerosol for delivery of the droplets to the alveoli, one is confronted with several problems that prevent a simple scaling-down of current designs to arrive at such ultra-small droplet volumes.
For example, ejection of single droplets in the tens of femtoliters size range requires extremely small liquid chambers that have critical dimensions that must be carefully controlled during the fabrication process.
The present invention is directed to the manufacture and use of a thermal-type drop generator for ejecting droplets of liquid having ultra-small volumes. In one preferred embodiment of the present invention the drop generator includes an ultra-small liquid chamber defined in part by an orifice member. Removable material is used in fabricating the chamber. The material is sized to match the chamber shape, and it supports the orifice member during processing of the material that makes up the orifice member. The use of such removable material is one of the features of the present invention for producing a drop generator for ejecting the ultra-small droplets.
Methods and apparatus for carrying out the invention are described in detail below. Other advantages and features of the present invention will become clear upon review of the following portions of this specification and the drawings.